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  • HEPATITIS WEB STUDY HEPATITIS C ONLINE

    Treatment of Chronic HCV Genotype 4

    Robert G. Gish MD Staff Physician, (Consultant) Stanford University Medical Center

    Senior Medical Director, St Josephs Hospital and Medical Center, Liver Program, Phoenix, Arizona

    Clinical Professor (Adjunct) of Medicine, University of Nevada, Las Vegas

    Medical Director, Hepatitis B Foundation

    Vice Chair, Executive Committee, National Viral Hepatitis Roundtable (NVHR)

    Last Updated: October 19, 2015

  • • Background and Definitions

    • Initial Treatment and Retreatment of Prior Relapsers

    • Retreatment of Prior Nonresponders

    • Issues and Controversies

    • Future Therapies

    • Summary

    Treatment of Chronic HCV Genotype 4

  • Background and Definitions TREATMENT OF CHRONIC HEPATITIS C: GENOTYPE 4

  • Treatment of Chronic HCV Genotype 4

    Background

    • HCV infects ~ 5 million people in the US today

    • Genotype 4 accounts for about 1-2% of HCV infections in US

    • Genotype 4 very important in Egypt, Saudi Arabia, North Africa, and

    Southern Europe and immigrants from these regions

    • Approximately 70% of patients with genotype 4 HCV have moderate to

    severe steatosis with or without sinusoidal fibrosis (similar to GT3)

    • Historic SVR rates with IFN-based therapy between GT1 and GT 2,3

  • Initial Treatment TREATMENT OF CHRONIC HEPATITIS C: GENOTYPE 4

  • Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org).

    AASLD/IDSA/IAS-USA 2015 HCV Treatment Recommendations

    Genotype 4 Chronic HCV: Initial Treatment

    Genotype 4 HCV: Initial Treatment

    Recommended Regimens

    Ledipasvir-Sofosbuvir x 12 weeks

    Ombitasvir-Paritaprevir-Ritonavir + Ribavirin x 12 weeks

    Sofosbuvir + Ribavirin x 24 weeks

    Alternative Regimen, Patients Eligible to Receive Interferon

    Sofosbuvir + Ribavirin + Peginterferon x 12 weeks

    http://www.hcvguidelines.org

  • Treatment-Naïve & Prior Relapsers with GT4 Chronic HCV

    Key Studies that Support Treatment Recommendations

    • Ledipasvir-Sofosbuvir - NIAID Synergy (Genotype 4)

    • Ombitasvir-Paritaprevir-Ritonavir - PEARL-I

    • Sofosbuvir + Ribavirin - Egyptian Ancestry

    • Sofosbuvir + Ribavirin + Peginterferon - NEUTRINO

  • Source: Kohli A, et al. Lancet Infect Dis. 2015:15:1049-54.

    Ledipasvir-Sofosbuvir in Genotype 4

    NIAID SYNERGY (GT4) Trial: Features

    Genotype 4

    Treatment Naïve (n = 13)

    Treatment Experienced (n = 8)

    n = 21 Ledipasvir-Sofosbuvir

    Drug Dosing

    Ledipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once daily

    Week 0 2412

    SVR12

  • Ledipasvir-Sofosbuvir in Genotype 4

    NIAID SYNERGY (GT4) Trial: Results

    NIH SYNERGY: SVR 12, Intent to Treat Analysis

    Source: Kohli A, et al. Lancet Infect Dis. 2015:15:1049-54.

    95 92 100

    0

    20

    40

    60

    80

    100

    All Treatment-Naïve Treatment-Experienced

    P a

    ti e

    n ts

    ( %

    ) w

    it h

    H C

    V R

    N A

    < 4

    3

    IU /m

    l

    Ledipasvir-Sofosbuvir Treated Patients

    20/21*

    *1 patient did not complete 12 weeks of treatment due to drug non-adherence

    12/13* 8/8

  • Source: Hézode C, et al. Lancet. 2015;385:2502-9.

    Ombitasvir + Paritaprevir + Ritonavir +/- RBV in HCV GT4

    PEARL-I: Regimens

    n = 44 Ombitasvir + Paritaprevir +

    Ritonavir SVR12

    n = 42 Ombitasvir + Paritaprevir +

    Ritonavir + Ribavirin SVR12

    Week 0 2412

    Drug Dosing

    Ombitasvir (25 mg once daily), Paritaprevir (150 mg once daily), Ritonavir (100 mg once daily)

    Ribavirin (RBV): weight-based and divided bid (1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg)

    HCV Treatment Naïve GT4

    HCV Treatment Experienced GT4

    n = 49 Ombitasvir + Paritaprevir +

    Ritonavir + Ribavirin SVR12

  • Ombitasvir + Paritaprevir + Ritonavir +/- RBV in HCV GT4

    PEARL-I: Results

    PEARL-I: SVR 12 Rates (HCV RNA

  • Source: Ruane PJ, et al. J Hepatol. 2015;62:1040-6.

    Sofosbuvir and Ribavirin in HCV Genotype 4

    Egyptian Ancestry Trial: Design

    Drug Dosing

    Sofosbuvir: 400 mg once daily

    Weight-Based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

    SVR12

    SVR12 Sofosbuvir + RBV

    (n = 28)

    Sofosbuvir + RBV

    (n = 32) GT 4

    Naïve

    or

    Experienced

    0 24 36Week 12

  • Sofosbuvir and Ribavirin in HCV Genotype 4

    Egyptian Ancestry Trial: Results

    SVR 12 by Regimen Duration and Treatment Experience

    Source: Ruane PJ, et al. J Hepatol. 2015;62:1040-6.

    Treatment Naive Treatment Experienced

    79

    100

    59

    87

    0

    20

    40

    60

    80

    100

    SOF + RBV x 12 weeks

    SOF + RBV x 24 weeks

    SOF + RBV x 12 weeks

    SOF + RBV x 24 weeks

    P a ti

    e n

    ts w

    it h

    S V

    R 1

    2 (

    % )

    11/14 10/1714/14 13/15

  • Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.

    Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6

    NEUTRINO Trial: Design

    24Week 0 12

    Sofosbuvir + PEG + RBV SVR12

    Drug Dosing

    Sofosbuvir: 400 mg once daily

    Peginterferon alfa-2a: 180 µg once weekly

    Ribavirin (weight-based and in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

    Total N = 327

    (N = 28 for GT 4)

  • Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6

    NEUTRINO Trial: Results

    NEUTRINO: SVR 12 by Genotype

    Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.

    89 96

    100

    0

    20

    40

    60

    80

    100

    GT 1 GT 4 GT 5,6

    P a ti

    e n

    ts w

    it h

    S V

    R 1

    2 (

    % )

    GT = genotype

    261/292 27/28 7/7

  • Retreatment of Persons in Whom Prior Therapy Failed TREATMENT OF CHRONIC HEPATITIS C: GENOTYPE 4

  • Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org).

    AASLD/IDSA/IAS-USA 2015 HCV Treatment Recommendations

    Genotype 4 Chronic HCV: Retreatment, Prior Failure with PR

    Genotype 4 HCV: Retreatment, Prior Failure with Peginterferon + Ribavirin

    Recommended Regimens

    Ledipasvir-Sofosbuvir x 12 weeks

    Ombitasvir-Paritaprevir-Ritonavir + Ribavirin x 12 weeks

    Sofosbuvir + Ribavirin + Peginterferon x 12 weeks

    Sofosbuvir + Ribavirin x 24 weeks

    http://www.hcvguidelines.org

  • Retreatment of GT4 Chronic HCV

    Key Studies that Support Treatment Recommendations

    • Ledipasvir-Sofosbuvir - NIAID Synergy (Genotype 4)

    • Ombitasvir-Paritaprevir-Ritonavir - PEARL-I

    • Sofosbuvir + Ribavirin + Peginterferon - NEUTRINO (data for treatment-naïve patients)

    • Sofosbuvir + Ribavirin - Egyptian Ancestry

  • Ledipasvir-Sofosbuvir in Genotype 4

    NIAID SYNERGY (GT4) Trial: Results

    NIH SYNERGY: SVR 12, Intent to Treat Analysis

    Source: Kohli A, et al. Lancet Infect Dis. 2015:15:1049-54.

    95 92 100

    0

    20

    40

    60

    80

    100

    All Treatment-Naïve Treatment-Experienced

    P a

    ti e

    n ts

    ( %

    ) w

    it h

    H C

    V R

    N A

    < 4

    3

    IU /m

    l

    Ledipasvir-Sofosbuvir Treated Patients

    20/21*

    *1 patient did not complete 12 weeks of treatment due to drug non-adherence

    12/13* 8/8

  • Ombitasvir + Paritaprevir + Ritonavir +/- RBV in HCV GT4

    PEARL-I: Results

    PEARL-I: SVR 12 Rates (HCV RNA

  • Sofosbuvir and Ribavirin in HCV Genotype 4

    Egyptian Ancestry Trial: Results

    SVR 12 by Regimen Duration and Treatment Experience

    Source: Ruane PJ, et al. J Hepatol. 2015;62:1040-6.

    Treatment Naive Treatment Experienced

    79

    100

    59

    87

    0

    20

    40

    60

    80

    100

    SOF + RBV x 12 weeks

    SOF + RBV x 24 weeks

    SOF + RBV x 12 weeks

    SOF + RBV x 24 weeks

    P a ti

    e n

    ts w

    it h

    S V

    R 1

    2 (

    % )

    11/14 10/1714/14 13/15

  • Issues and Controversies TREATMENT OF CHRONIC HEPATITIS C: GENOTYPE 4

  • Issues and Controversies

    • Cost of Therapy

     What is real cost?

     Cost per cure?

     Discounts

    • When to Defer or Decline Therapy

     Decisions on when to warehouse if any?

     Noncompliance

     Short life span

    • (Non) Role of IL-28b Testing

    • Is the Degree of Liver Fibrosis useful to allocate treatment

     How to stage?

  • How is cost of therapy impacting treatment decisions?

  • Hepatitis C Genotype 4

    Costs of Different Regimens for Treatment of Geno